Peroxisome Proliferator Activated Receptors (PPAR's), alike glucocorticoid receptors, tretinoin receptors and thyroid receptors, are ligand-dependent transcription factors pertaining to intranuclear receptor superfamily. PPAR can be subdivided into three subtypes: PPARα, PPARγ and PPARδ (also known as PPARβ and NUC1), which are encoded by different genes. Moreover, PPARγ also have two isoforms, i.e., PPARγ1 and PPARγ2. These two proteins differ in their 30 amino acids at NH2-terminal, which are resulted from the alternative use of promoter and the differential splicing of nRNA (Vidal-Puig, J. Clin. Invest., 97:2553-2561, 1996).
PPARα is mainly expressed in the tissues, such as brown adipose tissue and liver, having high catabolic capacity for lipids, followed by kidney, heart and skeletal muscle (Endocnnology, 1995, 137, 354). It can positively or negatively control the expression of genes related to the metabolism and the intracellular transport of fatty acid (e.g. acyl CoA synthetase, fatty acid-binding protein and lipoprotein lipase) and of apolipoprotein (AI, AII, CIII) genes related to the metabolisms of cholesterol and neutral lipids PPARγ is found at high levels in adipose tissue and at lower levels in skeletal muscle, liver, colon, retina and immune system. Recently, it was found at high levels in macrophages, including atherosclerorotic foam cell. Of which, PPARγ2 was specifically expressed predominantly in adipose tissue. In contrast, PPARγ1 had a broad tissue expression, and was expressed at the highest levels in kidney, intestines and heart. PPARγ serves as a key regulator for adipocyte differentiation and expression of insulin-sensitive genes (J. Lipid Res., 1996, 37, 907).
PPARδ is expressed ubiquitously in the tissues of organisms with nerve cells as the center. At present, the physiological significance of PPARδ is still unclear.
Thiazolidinedione drugs, for example troglitazone and rosiglitazone, were clinically shown to be capable of enhancing insulin-action and reducing serum glucose in patients with Type 2 diabetes. It has been reported that thiazolidinediones are potent and selective activators of PPARγ and bind directly to the PPARγ receptor (J. M. Lehmann, et. al., J. Biol. Chem. 2953-12956, 270 (1995)).
Fibrates were widely used as a class of drugs for treating hyperlipidemia, which might lower serum triglycerides by 20-50%, lower LDLc by 10-15%, and increase HDLc by 10-15%. Experimental evidence indicated that the effects of fibrates on serum lipids were mediated through activation of PPARα. See, for example, B. Staels, et al., Curr. Pharm. Des., 7-14, 3(1), (1997). Activation of PPARα resulted in transcription of enzymes that increased fatty acid catabolism and decreased fatty acid re-synthesis in the liver (leading to decrease of triglyceride synthesis and VLDL production/secretion). In addition, activation of PPARα decreased production of apoC-111. The reduction in production of apoC-111 (an inhibitor of LPL activity) increased clearance of VLDL (J. Auwerx, et al., Atherosclerosis, J59-S37, 124 (Suppl), (1996)).
The results of the existing technology showed that a dual agonist of PPARα and PPARγ had additional advantage for reducing other abnormality, in particular increased triglyceride, concomitant with diabetes. See, for example, U.S. Pat. No. 5,478,852, WO 98/05331.